HIV-1 is one of the most genetically diverse pathogens on earth. In fact, some coding regions, such as envelope, can have more than 30% genetic difference between clades. The neurocognitive effects of clade B HIV-1 infection have been well characterized in the developed world; however, there continues to be controversy surronding the effect of non-clade B infection on the neurocognitive functioning. The overarching aims of the proposed study is to 1) characterize and compare the burden of HIV associated neurocognitive disorders (HAND) occurring among individuals living in Brazil, China, India, Romania and the United States and infected with CRF01_AE and clades B, C and F, and 2) evaluate the neurovirulent and neurotropic genotypic determinants between subtypes. Important research questions that remain unanswered include: How do the prevalence, nature and course of HAND in various parts of the world compare when analyzed by population and subtype? What specific viral genetic characteristics are associated with neurovirulence and seeding of the central nervous system (CNS)? The current proposal is designed to systematically address these issues by: 1) determining the differential effect of HIV subtype on neurocognitive performance by measuring HAND using standardized measures in previously established cohorts in Brazil (clades B and C), China (CRF01_AE and clades B and C), India (clade C), Romania (clade F) and the United States (clade B), 2) determining viral genetic motifs from HIV RNA that are conserved during HAND by subtype and by study population by performing clade-typing of study participants by generating population based sequences of the env and tat coding regions from HIV RNA and DNA extracted from blood, and 3) determining viral genetic motifs from HIV RNA that are conserved during CNS compartmentalization between clades B and C by performing clonal sequencing of the env and tat coding regions from HIV RNA extracted from paired blood and CSF samples collected from participants with clade B or C infection in Brazil, India and the United States. The comparison of the burden of HAND between groups infected with different HIV clades requires standardized procedures for the measurement of HAND within and across populations. Investigations into clade-specific genotypic determinants of HIV neuropathogenesis and neurotropism requires: 1) well-characterized study populations and biologic samples from study participants, 2) standardization of measurements of neurocognitive functioning, 3) high quality HIV RNA sequencing capability in all research study settings, 4) secure and reliable data management and communication capabilities for sequence and study data between participating sites, and 5) expertise in state-of- the-art genotypic analysis. Our group has demonstrated experience in each of these areas.